Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:16]([O:19][CH2:20][CH2:21][O:22][CH2:23]Br)(=[O:18])[CH3:17]>CN(C=O)C>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:23][O:22][CH2:21][CH2:20][O:19][C:16](=[O:18])[CH3:17])[CH:2]=1
Reactant: CC(=O)OCCOCBr
Reactant: c1cnc2[nH]cnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOCn1cnc2cccnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 41 %

Procedure:
To a solution of 1.0 g (8.39 mmol) 3H-imidazo[4,5-b]pyridine in 20 ml DMF kept under argon at 0° C. 0.94 g (8.39 mmol) potassium tert-butoxide were added. The solution was warmed to room temperature and after 1 hour a solution of 1.74 g (8.8 mmol) (2-acetoxyethoxy)methyl bromide in 5 ml DMF was added dropwise over half an hour. The reaction was stirred at room temperature for 20 hours and then poured onto 75 ml of ice water. The mixture was extracted twice with 50 ml ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, gradient DCM, DCM/MeOH 95/5 and 9/1) to afford 0.81 g (41%) of the desired product. MS(ISP): 236.2 [MH]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[S:14][CH:15]=[C:16](/[CH:18]=[CH:19]/[C:20](Cl)=[O:21])[N:17]=1>O.CC(C)=O.O1CCOCC1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[S:14][CH:15]=[C:16](/[CH:18]=[CH:19]/[C:20]([N:1]=[N+:2]=[N-:3])=[O:21])[N:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=NC(=O)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a cooled (0° C.) solution of sodium azide (6.2 g, 95 mmol) in water (100 mL) and acetone (100 mL) was added a solution of (E)-3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acryloyl chloride (6.0 g, 19 mmol) in dioxane (100 mL) dropwise. After addition, the resulting mixture was stirred for 1 hour at 0° C. The reaction was quenched with water (50 mL) and extracted with EtOAc (3×80 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The resultant residue was purified via silica gel column chromatography eluting with EtOAc/petroleum ether (1:8) to afford the desired product as a yellow solid (6.0 g, 98% yield). LCMS (ESI) m/z: 325.0 [M+H+].
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[C:39]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][C:48](=[O:50])[NH2:49])[NH2:46])([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][C:48](=[O:50])[NH2:49])[NH:46][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13])([CH3:42])([CH3:40])[CH3:41]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1

Procedure:
Analogously to Example 100, 5.45 g (31.4 mmol) of quinaldic acid in 161 ml of THF are reacted with 7.08 g (34.3 mmol) of DCC, 4.63 g (34.3 mmol) of HOBT and 5.38 g (28.6 mmol) of (L)-asparagine tert-butyl ester (Bachem, Bubendorf/Switzerland). Filtration, extraction and column chromatography (SiO2, ethyl acetate/hexane 3:1) yields the pure title compound: TLC Rf (C')=0.15; tRet (V)=12.2 min; FAB-MS (M+H)+ =344.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=3[NH:17][C:16]2=[O:25])[CH2:11][CH2:10]1)=[O:5].[C:31](OC(=O)C)(=[O:33])[CH3:32].[OH-].[NH4+]>O>[C:31]([NH:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=3[NH:17][C:16]2=[O:25])[CH2:11][CH2:10]1)=[O:5])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 0.8 parts of 2-amino-N-{2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1yl)-1-piperidinyl]ethyl}-4-fluorobenzamide, 1 part of acetic acid anhydride and 10 parts of water is stirred for 30 minutes in a water-bath at 80°-90° C. The reaction mixture is cooled, alkalized with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 0.5 parts of 2-(acetylamino)-N-{2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-4-fluorobenzamide; mp. 196.5° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(O)(=O)C>O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccccc3)on2)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2cc(-c3ccccc3)on2)cc1
Yield: 95.3 %

Procedure:
A mixture of methyl 4-(5-phenyl-3-isoxazolyl)benzoate (1.05 g), 6 M hydrochloric acid (10 ml) and acetic acid (20 ml) was heated under reflux for 5 hrs. After cooling, the reaction mixture was poured into water, and the crystals were washed with water to give 4-(5-phenyl-3-isoxazolyl)benzoic acid (0.95 g, yield 95%). Recrystallization from N,N-dimethylformamide-water gave colorless prism crystals. melting point: 297–298° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][OH:27])=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:28])[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1O.[NH:57]1[CH2:61][CH2:60][CH2:59][CH2:58]1.[C:62]([OH:67])(=[O:66])[C:63]([OH:65])=[O:64]>ClCCl.C(O)C>[C:62]([OH:67])(=[O:66])[C:63]([OH:65])=[O:64].[CH3:48][O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[O:27][CH2:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([N:57]3[CH2:61][CH2:60][CH2:59][CH2:58]3)=[CH:17][C:18]([CH3:28])=[N:19]2)=[CH:24][CH:23]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)c2ccc(CO)cc2n1
Reactant: COc1ccccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C(O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccccc1OCc1ccc2c(N3CCCC3)cc(C)nc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
Diisopropylazodicarboxylate (97 mg, 0.48 mmol) was added dropwise at r.t. to a solution of (4-chloro-2-methyl-quinolin-7-yl)-methanol (example 2c, 100 mg, 0.48 mmol), triphenylphosphine (126 mg, 0.48 mmol), 2-methoxyphenol (60 mg, 0.48 mmol) in dichloromethane (2.5 mL). After shaking 24 h at r.t., the solvent was evaporated, and the residue was taken up in pyrrolidine (1.37 g, 19.2 mmol) and shaken for 23 h at 80° C. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane, the organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) yielded a yellowish solid which was dissolved in ethanol and treated with 20% ethanolic oxalic acid solution. The precipitate was collected by filtration and dried to afford the title compound (90 mg, 43%). Off-white solid, ISP-MS: m/e=349.4 ([M+H—C2H2O4]+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1.B(Br)(Br)Br.[Cl:29]CCl>>[ClH:29].[ClH:29].[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccn2c(C)c(CCc3ccc4nc(N)sc4c3)nc2c1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: Cc1c(CCc2ccc3nc(N)sc3c2)nc2cc(O)ccn12
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The mixture of 2-amino-6-[2-(7-methoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzothiazole (2.3 g) and boron tribromide (6.4 ml) in dichloromethane (115 ml) was stirred for 20 hours at ambient temperature and the solvent was evaporated in vacuo. A mixture of obtained residue and water was adjusted to pH 7.5 with 20% potassium carbonate aqueous solution and resulting precipitate was collected by filtration and dried. The residue was purified by alumina column chromatography eluting with a solution of chloroform and methanol (4:1, V/V). The fractions containing object compound were concentrated in vacuo. To a mixture of obtained residue and ethanol (3 ml) was added conc. hydrochloric acid (0.2 ml) and the mixture was stirred for 30 minutes at ambient temperature. The resulting precipitate was collected by filtration and dried to give 2-amino-6-[2-(7-hydroxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzothiazole dihydrochloride (0.22 g).
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#[N:17])C.[Cl:18][C:19]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:20]=1N>C1(S(O)(=O)=O)C=CC=CC=1.O>[CH:1]([NH:17][C:23]1[CH:22]=[CH:20][C:19]([Cl:18])=[CH:25][C:24]=1[I:26])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(I)cc1Cl
Agent: O=S(=O)(O)c1ccccc1
Solvent: O
Product: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of benzhydrol (13.5 g, 73.3 mmol) and acetonitrile (56 mL) was added over 1 h to a warm (80° C.), stirred solution of 2-chloro-4-iodoaniline (16 g, 63.1 mmol), benzenesulfonic acid (0.323 g, 2.0 mmol) and acetonitrile (53 mL). The solution was maintained at 80° C. for an additional 2.5 h. The mixture was allowed to cool to room temperature. Water (31 mL) was added over 1 h to the stirred mixture. The mixture was stirred for 2 h at room temperature. The solid product was collected by filtration. The solid product was combined with methanol (67 mL) and warmed to reflux for 30 m. The mixture was allowed to cool to room temperature. The purified product was collected by filtration, washed with methanol (2×10 mL) and vacuum dried to give 22.3 g of benzhydryl-(4-chloro-2-iodo-phenyl)-amine with 99% purity (as determined by HPLC). Mp 107-110.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].N12CCCN=C1CCCCC2.[Cl-].[Na+]>ClCCl>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1)[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cn[nH]c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a mixture of 1H-pyrazole-4-carbaldehyde (5.5 g) and ethyl bromoacetate (19.0 g) in dichloromethane (150 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10 ml) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes, and the reaction was stopped by addition of a saturated aqueous sodium chloride solution. The products were extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate (1:3) as the eluent to afford the title compound as a colourless oil (8.09 g, yield: 78%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:11]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: BrCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 61.5 %

Procedure:
A mixture of 2,4,5-triphenylimidazole (11.5 g), 1,7-dibromo-heptane (50 g) and potassium carbonate (27 g) in dry butanone (250 ml) was heated at reflux for 20 hours. The mixture was filtered and the filtrate evaporated to an oil. Chromatography on silica gel (hexane/ethyl acetate) and recrystallisation from hexane gave 1-(7-bromoheptyl)-2,4,5-triphenylimidazole (11.3 g, 61.4%) as a colourless solid, m.p. 69°-71°.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[F:22][C:23]1([F:33])[O:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([NH2:32])[C:25]=2[O:24]1>>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:32][C:31]4[C:25]5[O:24][C:23]([F:33])([F:22])[O:27][C:26]=5[CH:28]=[CH:29][CH:30]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1cccc2c1OC(F)(F)O2
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cccc4c3OC(F)(F)O4)ncc21

Procedure:
The title compound was synthesized from 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one and 2,2-difluorobenzo[d][1,3]dioxol-4-amine using the procedure described in the general Buchwald Reaction Scheme. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.84 (m, 9H) 3.97 (t, J=14.40 Hz, 2H) 4.50-4.70 (m, 1H) 7.14 (d, J=2.27 Hz, 1H) 7.31 (dd, J=7.45, 2.15 Hz, 1H) 8.21 (s, 1H) 9.39 (s, 1H). [M+H] calculated for C20H19F4N5O3, 454. found 454.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Cl[C:13]1[CH:14]=[C:15]([CH:19]=[C:20](Cl)[CH:21]=1)[C:16](Cl)=[O:17].C(N([CH2:28][CH3:29])CC)C>C1COCC1>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:16]([C:15]3[CH:19]=[CH:20][C:21]([C:29]4[CH:28]=[CH:9][CH:10]=[CH:2][CH:3]=4)=[CH:13][CH:14]=3)=[O:17])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCC2=O)c1ccc(-c2ccccc2)cc1
Yield: 144 %

Procedure:
Reaction of 5-amino-indan-1-one (73 mg, 0.50 mmol) in THF (6 mL) with 3,5-dichlorobenzoyl chloride (136 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave biphenyl-4-carboxylic acid (1-oxo-indan-5-yl)-amide (115 mg, 0.36 mmol, 72% yield) as a brown powder after purification by washing the crude product with ethyl acetate.
Reaction SMILES: [CH3:1][C:2]([C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)([CH3:4])[CH3:3].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:4][C:2]([C:5]1[NH:13][C:8]2=[N+:9]([O-:25])[CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc2cccnc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc2ccc[n+]([O-])c2[nH]1
Temperature: 25 °C

Procedure:
2-(1,1-Dimethylethyl)-1H-pyrrolo[2,3-b]pyridine (10 g, 57 mmol) was dissolved in ethyl acetate:DCM (400 ml, 1:1, v/v), cooled to ˜0° C. in an ice bath and treated by dropwise addition of m-chloroperbenzoic acid (15.85 g, 69.5 mmol). The reaction was warmed to room temperature over 3 hours then treated with 30% potassium carbonate (aq) (150 ml). The organic layer was separated and the aqueous washed with further DCM (2×100 ml). The combined organic layers were washed with a sodium metabisulphite solution, dried then evaporated to give title compound, 11.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[O:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>>[CH2:20]([NH:22][C:23]([N:16]1[C:17]([CH3:19])=[CH:18][C:14]([O:13][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][C:4]=2[Cl:12])=[N:15]1)=[O:24])[CH3:21]
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CCN=C=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Yield: 62.8 %

Procedure:
3-(2,6-Dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole was reacted with ethyl isocyanate in the same manner as in Example 17 to give a white solid of N-ethyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (5.37 g, yield: 62.8%). Melting point: 80˜82° C., 1H-NMR (Acetone-d6, Acetone, ppm): δ1.10 (t, J=7.2 Hz, 3H), 2.55 (d, J=0.8 Hz, 3H), 3.25 (dq, J=6.1 and 7.2 Hz, 2H), 5.71 (q, J=0.8 Hz, 1H), 7.37˜7.48 (brt, 1H, J=6.1 Hz), 7.67 (q, 2H, JHF=0.7 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18](CSCCOC3C=CC=CC=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8].[O:33]([CH2:40][CH2:41][S:42][CH2:43]C1C=C(C2C=CC=C(C(O)=O)C=2)C=CC=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:32][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:20]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: O=C(O)c1cccc(-c2cccc(CSCCOc3ccccc3)c2)c1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1cccc(-c2cccc(CSCCOc3ccccc3)c2)c1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (0.7 g, 1.92 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.32 g, 1.96 mmol, 1.02 eq.), and 3-(dimethylamino)propylamine (0.30 g, 2.30 mmol, 1.2 eq.) as described. When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH2:26][CH3:27])[CH:20]=[CH:19]4)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH:39]=[C:38]([C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)[CH2:37][CH2:36]1>C1COCC1.CN(C=O)C>[CH2:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:35]4[CH2:36][CH:37]=[C:38]([C:41]5[C:49]6[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=6)[NH:43][CH:42]=5)[CH2:39][CH2:40]4)[O:28][C:17]3=2)[N:22]=1)[CH3:27]
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CCc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1ccc2c3c(ccc2n1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 25 °C

Procedure:
To a solution of (2R)-8-ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.60 g, 1.5 mmole) and potassium carbonate (0.65 g, 4.70 mmole) in 30 mL of 1:1 THF/DMF was added 0.90 g (4.5 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The mixture was heated at reflux under nitrogen for 6 hours. After cooling to room temperature, the mixture was concentrated to dryness under vacuum and the residue column chromatographed on silica gel using first methylene chloride to elute impurities and then 3% methanol in methylene chloride to elute the product. The product-containing fractions were concentrated in vacuum and the residue recrystallized from ethanol to give 0.42 g of the (S)-enantiomer of the title compound as a yellow solid (m.p. 190° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH:36]([CH3:38])[CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH:36]([CH3:38])[CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)Oc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-isopropoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0740 g, 0.143 mmol) in methylene chloride (2 mL) was added with trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was added with water (6 mL) and saturated aqueous sodium hydrogencarbonate (6 mL), and thereby made basic, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was subjected to suction filtration, and the resulting solid was washed with water to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-isopropoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0301 g, 50%).
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([CH3:22])([CH3:21])[CH2:7]1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:5]([CH:6]1[CH2:7][C:8]([CH3:21])([CH3:22])[N:9]([O:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[C:10]([CH3:13])([CH3:12])[CH2:11]1)[C:30](=[O:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCN(C(=O)CCC(=O)O)C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Reaction time: 6 h
Yield: 45.5 %

Procedure:
A solution of 10.2 grams (33 mmol) of 4-n-butylamino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine (prepared in Example 8), 3.3 grams (33 mmol) of triethylamine, and 30 ml of tetrahydrofuran is added to a solution of 3.0 grams (30 mmol) of succinic anhydride in 20 ml of tetrahydrofuran over a 5-minute period. The reaction mixture is stirred for six hours and then diluted with ethyl acetate (200 ml). The organic solution is washed with 1N hydrochloric acid (2×50 ml), washed with water (50 ml), washed with saturated sodium chloride solution (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oil which crystallizes on standing. Recrystallization from heptane affords 5.6 grams (46% yield) of the title compound as a white solid melting at 110°-113° C.